Energy decomposition and waterswapping analysis to investigate the SNP associated DPD mediated 5-FU resistance.

5-fluorouracil is an essential component of systemic chemotherapy for colon, breast, head, and neck cancer patients. However, tumoral overexpression of the dihydropyrimidine dehydrogenase has rendered 5-FU clinically ineffective by inactivating it to 5'-6'-dihydro fluorouracil. The responses to 5-FU in terms of efficacy and toxicity greatly differ depending upon the population group, because of variability in the DPD activity levels. In the current study, key active site amino acids involved in the 5-FU inactivation were investigated by modelling the 3D structure of human DPD in a complex with 5-FU. The identified amino acids were analyzed for their possible missense mutations available in dbSNP database. Out of 12 missense SNPs, four were validated either by sequencing in the 1000 Genomes project or frequency/genotype data. The recorded validated missense SNPs were further considered to analyze the effect of their respective alterations on 5-FU binding. Overall findings suggested that population bearing the Glu611Val DPD mutation (rs762523739) is highly vulnerable to 5-FU resistance. From the docking, electrostatic complementarity, dynamics, and energy decomposition analyses it was found that the above mutation showed superior scores than the wild DPD -5FU complex. Therefore, prescribing prodrug NUC-3373 or DPD inhibitors (Gimeracil/3-Cyano-2,6-Dihydroxypyridines) as adjuvant therapy may overcome the 5-FU resistance.

Picrorhiza kurroa (Kutaki) Royle ex Benth as a hepatoprotective agent--experimental & clinical studies.

Picrorhiza kurroa (Pk), a known hepatoprotective plant, was studied in experimental and clinical situtations. The standardization of active principles--Picroside 1 and 2 was done with High Performance Liquid Chromatography. Picroside 1 ranged from 2.72 to 2.88 mg/capsule and picroside 2 from 5.50 to 6.00 mg/capsule. In the galactosamine-induced liver injury in rats, Pk at a dose of 200 mg/kg p.o. showed a significant reduction (p < 0.05) in liver lipid content, GOT and GPT. In a randomised, double-blind placebo controlled trial in patients diagnosed to have acute viral hepatitis (HBsAg negative), Pk root powder 375 mg three times a day was given for 2 weeks (n = 15) or a matching placebo (n = 18) was given. Difference in values of bilirubin, SGOT and SGPT was significant between placebo and Pk groups. The time in days required for total serum bilirubin to drop to average value of 2.5 mg% was 75.9 days in placebo as against 27.44 days in Pk group. The present study has shown a biological plausability of efficacy of Pk as supported by clinical trial in viral hepatitis, hepatoprotection in animal model and an approach for standardizing extracts based on picroside content.

A two-stage clinical trial of Phyllanthus amarus in hepatitis B carriers: failure to eradicate the surface antigen.

BACKGROUND: There have been conflicting data in literature about the value of Phyllanthus amarus in treating hepatitis B virus-related disorders. AIM: To evaluate the role of Phyllanthus amarus in eradication of the virus in hepatitis B carriers. METHODS: Phyllanthus amarus was administered to 30 asymptomatic carriers of hepatitis B surface antigen (HBsAg) in a dosage of 250 to 500 mg thrice daily for 4 to 8 weeks. RESULTS: None of the 30 subjects cleared HBsAg. Phyllanthus amarus was well tolerated, with no clinical side effects or changes in the organ profiles for safety evaluation. CONCLUSION: Phyllanthus amarus is not effective in clearing HBsAg in asymptomatic carriers of the antigen.